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Drugs that Inhibit Cell wall synthesis • Beta-lactams – Penicillin family – Cephalosporin family – Carbapenems and Monobactams – Β-lactamase inhibitors • Vancomycin • Bacitracin • These drugs are bactericidal – Failure of the cell wall results in death 1 2 Penicillin Family • Amdinocillin Ampicillin Augmentin* Azlocillin Carbenicillin Cloxacillin Cyclacillin Dicloxacillin Floxacillin Amoxicillin Methicillin Mezlocillin Nafcillin Oxacillin Piperacillin Sulbactam (beta-lactamase inhibitor) Ticarcillin Timentin* * Combo with beta-lactamase inhibitor http://www.wheelessonline.com/ortho/penicillin_family 3 Development of Beta-lactam families • Target different species – Not all drugs can pass through Gram – OM – “Penicillin binding proteins” (PBPs) vary – Specificity of beta-lactamases varies – Beta-lactam ring sensitive to hydrolysis; improved acid stability for oral administration • Thus drugs differ – In organisms that they affect – General pharmacokinetics, administration – Type and extent of resistance against 4 Peptidoglycan Synthesis-1 • • • • 5 NAM and peptide with D-ala connected Attached to lipid carrier: bactoprenol-phosphate NAG added (UDP-NAG) to complete unit NAG-NAM-peptide transported through cell membrane to cell wall Peptidoglycan Synthesis-2 6 • new NAM-NAG unit attached, autolysins cut old wall • crosslinking completed 7 8 Beta-Lactam reaction with transpeptidase D-Ala- D-Ala dipeptide http://www.antiinfectieux.org/antiinfectieux/Assets/PLS/Beta-lactames/betalactames-mecanisme-action-2-600.gif http://www-organik.chemie.uniwuerzburg.de/ak_engel/Sebastian/Bilder/diplom5.gif 9 Consequences of mode of action • Beta-lactam reacts with serine in active site – Irreversible binding, inactivates enzyme – Also inactivates drug, used up in reaction • Target is in cell wall – External beta-lactamases destroy drug before target is reached 10 11 Vancomycin, a glycopeptide http://www.chemicalforums.com/index.php?page=molecules Mechanism of vancomycin 12 vancomycin Binds to peptide with high affinity via 5 hydrogen bonds http://www.ratsteachmicro.com/Assets/Antibiotics_combined/vancomycin.gif Bacitracin Peptide antibiotic Isolated from Bacillus from a patient named Tracy. http://smccd.net/accounts/case/biol230/b acitracin/bacitracin2.gif With divalent cation, binds to bactoprenolpyrophosphate, prevents dephosphorylation of carrier, blocks PG biosynthetic pathway. 13 14 Resistance to beta-lactams 15 • Beta-lactamases – Numerous types present among bacteria – Found on Gram – as well as Gram + – Coded for plasmids or by chromosomal genes – Some sensitive to beta-lactamase inhibitors, some not • Resistance in Gram - : failure to reach target – Passage through OM is through porins – Although porins are not highly selective, some drugs cannot pass or the porins become mutated Resistance to beta-lactams-2 16 • Failure to bind to target – Wide variety of bacteria, wide assortment of PBPs – Mutations occur in PBP genes • About MRSA – Staph aureus originally susceptible to penicillin, 1940s; by 1950s, no longer – About 40% of Staph aureus now resistant to methicillin and other beta-lactamse resistant drugs – Has acquired a gene for a PBP that poorly binds beta-lactams, causing resistance Resistance to vancomycin 17 • A cluster of genes that senses the presence of vancomycin, activates an enzyme that replaces the D-ala-D-ala dipeptide with D-ala-D-lactate. – Interesting evolutionary history – Gene cluster probably originated with producing streptomyces – Known to be present in Enterococci, probably passed by conjugation to Staph aureus. – http://www.medscape.com/viewarticle/473156 proposes spread of resistance in animal feed Pharmacokinetics • Beta-lactams differ greatly in – Route of administration (oral absorption) – Binding to serum proteins – Metabolism and extent of renal excretion • Tend to be excreted unchanged (good for treatment of urinary tract infections) • Benzathine penicillin, im injection – Half life of 14 days – Mainstay of health clinics for treatment of syphilis 18 About combinations • Beta-lactamase inhibitors – Clavulanate, sulbactam, and tazobactam – Some have weak antibiotic activity alone – Bind to beta-lactamases and inhibit them – Beta-lactamase inhibitors paired with beta-lactam antibiotics which then do the heavy lifting • Typical example – Clavulanate + amoxicillin = Augmentin 19 Toxicity 20 • Beta-lactams show wide range – Diarrhea and other GI problems are most common • Problems with upsetting normal ecology • Most significant danger: pseudomembranous colitis caused by Clostridium difficile – Delayed type hypersensitivity much more likely than immediate type (IgE), fortunately Toxicity-2 • Vancomycin – Hypersensitivity reactions with rash and hypotension – Ototoxicity, phlebitis • Bacitracin – Topically administered, few problems – Cannot be taken internally because of inhibition of sterol synthesis, nephrotoxicity 21